Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism
Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism
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DOI：
10.1007/s11095-011-0420-y
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发表时间：
2011-08-01
影响因子：
3.7
通讯作者：
Sun, Yu-Nien
中科院分区：
文献类型：
--
作者：
Wang, Yow-Ming C.;Sloey, Bethlyn;Sun, Yu-Nien
罗米普替姆是一种治疗成人免疫性血小板减少症(ITP)的新型血小板生成素模拟剂，其作用机制与血小板生成素相似，但没有序列同源性。从结构上讲，它是一种含有血小板生成素模拟肽和人免疫球蛋白Fc部分的多肽(1)。我们研究了罗米普替丁在啮齿动物体内的药代动力学，重点是清除机制。在四种模型中进行了适当对照的研究：FcRN基因敲除小鼠、血小板减少小鼠、脾切除大鼠和双侧肾切除大鼠。本文研究了罗米普替丁在正常大鼠体内的分解代谢。第一种分析方法确定完整/活性罗米普司汀的浓度，第二种方法确定罗米普西汀及其分解代谢降解物的总和。FcRn相互作用会导致长期暴露。血小板参与靶向介导的消除，这是一个可饱和的过程，在低剂量时更为突出。脾切除不影响罗米普替丁在大鼠体内的药代动力学，这一观察结果并不出人意料。在大鼠肾切除实验中，在较大剂量的罗米普替丁作用下，罗米普罗替丁的暴露剂量会有较大幅度的增加，这种非线性可能是由于竞争通路饱和所致。分解代谢在罗米普替明的清除中起主要作用，罗米普西汀清除涉及多种机制，包括一条非线性途径。因此，不同机制的相对贡献似乎是剂量依赖的。
Romiplostim, a treatment for adults with immune thrombocytopenia (ITP), is a novel thrombopoietin mimetic agent with a similar mechanism of action as thrombopoietin with no sequence homology. Structurally, it is a peptibody containing thrombopoietin mimetic peptides and the Fc portion of human IgG(1). We investigated romiplostim pharmacokinetics in rodents with a focus on the clearance mechanism.Studies with appropriate controls were conducted in four models: FcRn knockout mice, thrombocytopenic mice, splenectomized rats, and bilateral nephrectomized rats. Catabolic breakdown of romiplostim was investigated in normal rats. The primary analytical method determines the intact/active romiplostim concentration, and the secondary method determines the sum of romiplostim and its catabolic degradants.FcRn interaction results in prolonged exposure. Platelets are involved in the target-mediated elimination, a saturable process and more prominent at low dose. Splenectomy does not affect the romiplostim pharmacokinetics in rats, an observation not unexpected. Nephrectomy in rats results in a greater increase of romiplostim exposure at a higher romiplostim dose, a nonlinearity likely due to saturation of competing pathway. Catabolism plays a major role in romiplostim elimination.Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent.